Two strategies will be employed to evaluate gene therapy approaches in the well-characterized simian immunodeficiency virus (SlV)/rhesus macaque animal model for AIDS pathogenesis. To accomplish these objectives a retrovirus vector encoding a transdominant HIV-1 rev gene that can inhibit SIV replication in rhesus peripheral blood mononuclear cells (PBMCs) will be utilized to genetIcally modIfy fetal liver hematopoietic stem cells (FLHSCs). For the first strategy, retrovirus-mediated transduced (RMT) FLHSCs will be transplanted in utero into a recipient rhesus macaque fetus. The value of a gene therapy approach to inhibit AIDS is only feasible if all the cells and tissues the virus is capable of infecting and replicating contain the anti-viral gene. Initially, infants who have received genetically modified stem cells in utero and survived to term will be evaluated for the presence and expression of the transdominant HIV-1 rev gene in the cells and tissues known to harbor SIV replication. The immune function of the animals will be evaluated, since it will have been genetically modified by a retrovirus. PBMCs will be obtained from the animals demonstrating stable gene transfer and infected with SIV in vitro to evaluate the anti-viral effect. Control rhesus macaque infants and infants harboring the transdominant rev gene will be infected with SlVmac239 and evaluated for virus load, CD4/CD8 ratios, and clinical disease progression. Death of the infected infants and time until death will be recorded and used as the measures to define the therapeutic potential. In the second strategy, RMT FLHSCs will be transfused into uninfected and SIV-infected animals that have received a lethal dose of irradiation. Similar parameters will be evaluated as described for the first strategy to assess the clinical relevance of this gene therapy approach. Taken together, these two approaches should shed considerable light on the efficacy of the transdominant rev gene as a reagent for gene therapy treatment for AIDS.